This Component 4 presents the continuation of the QTL mapping efforts of the QTL mapping efforts of Component 7 of our present Center grant. In the renewal, we propose to use populations derived from two presently existing long-term selectively-bred-lines the FAST and SLOW lines bred for increased and reduced sensitivity to ethanol-induced locomotor activation, respectively, and the HOT and COLD lines bred for minimal or severe ethanol-induced hypothermia (body temperature loss). Both projects were developed beginning with an HS foundation population, which in turn was derived from an eight-way cross of inbred strains. [Continued studies of the third long-term selection project, WSP/WSR, are now part of an RO1 application in preparation (PI: K.Buck)]. Because of the markedly different gene pools in our HS-compared to our B6-, D2- derived populations, we expect most unique QTLs to emerged in this Component for these traits. In the first four years of Center support, a full genome scan was carried out as part of present Component 7 in the search for QTLs influencing both acute ethanol-induced hypothermia (HOTxCOLD F2) and chronic ethanol withdrawal severity (WSPxWSR F2). The third mapping project involving locomotor activation (FASTxSLOW F2) will be finished in the final year of our present support. Thus far, 8 suggestive (P<.0015) and one significant (p<.00005) QTLs influencing either hypothermia or withdrawal have been detected and mapped to broad chromosomal regions. We propose an additional F2 population for hypothermia, and another for locomotor activation, to be tested to increase the number of significant QTLs, and to test for modifier loci of known QTLs, a form of epistasis. For the three most important QTLs per trait, congenic strains will be developed to isolate individual QTLs, and the interval specific strain (ISCS) used to attain high resolution (1 cM) mapping for each QTLs. In addition, a systemic genome-wide search will be carried out to find modifier loci of all apparent QTLs attaining a nominal p,.05. Because the risk of false-positive modifiers (an epistatic interaction) is substantial, each modifier locus will be specifically tested in new F2 intercross to confirm their existence. This component will be active in all years of requested Center support.